11 -Methyl-11 -azabicyclo

There are eight possible stereoisomeric forms of methyl 3-(benzoyloxy)-8-methyl-azabicyclo[3.2.1 ]octan-2-carboxylate, of which one, R-cocaine, is simply referred to as cocaine. Chemically, cocaine is known as 2R-carbomethoxy-3S-benzyloxy-1 R-tropane. Cocaine is naturally occurring in a variety of plants belonging to the Erythroxylon coca species, which is indigenous to some countries in South America. In addition to its stimulant actions, cocaine possesses vasoconstrictor actions and is a local anesthetic it has served as a template for the development of other therapeutically useful agents, including local anesthetics and S-HTs serotonin antagonists. 

The nomenclature of penicillins requires special comment. Compound (2) can be named as follows (a) penicillin G (b) benzylpenicillin (note that the term penicillin may refer to the compound class (1), to the structural fragment (3) or, especially in the medical literature, to compound (2) itself) (c) 6/3-phenylacetamidopenicillanic acid (d) 2,2-dimethyl-6/3-phenylacetamidopenam-3a -carboxylic acid (e) (2S,5i ,6i )-3,3-di-methyl-7-oxo-6-(2-phenylacetamido)-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid and (f) [2S-(2a,5a,6/3)]-3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-4-thia-l-azabicyclo-[3.2.0]heptane-2-carboxylic acid. The numbered system shown in (2) is the one most commonly used in the penicillin literature and will be used in this chapter note that different number is used when (2) is named according to (e) and (f) above. 

Oxa-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 8-oxo-7-(phenylacetamido)-3-(5-tetrazolylthiomethyl)-, diphenyl methyl ester X-ray, 7, 349 (B-82MI51206)... 

Azabicyclo[2.1.0]pentane-3-carboxylic acid antimicrobial activity, 7, 346 l-Azabicyclo[3.3.3]undecane — see Manxine 1 - Aza-2-boracyclohexane, 1 -methyl-synthesis, 1, 647... 

The bicyclic amine 11-methyl-l l-azabicyclo[5.3.1]hendecanc (71) provided a model system in which the hydrogens on the equivalent a-tertiary-carbon atoms cannot be trans to the nitrogen-mercury bond in the mercur-ated complex and in which epimerization at these a carbons is impossible (77). This bicyclic system is large enough to accommodate a... 

Oxidation of 8-( 1 -methylethenyl)-2-oxo-7-thia-1 -azabicyclo[4.3.0]octa-3,5-diene-5,8-dicarboxylate (104) and its 3,4-dihydro derivative in CHCI3 with peracids (w-chloroperbenzoic acid and CF3CO3H) at room temperature gave diethyl 3-methyl-6-oxo-2/7,6//-pyrido[2,l-Z)][l,3]thiazine-4,9-dicarboxylate and its 7,8-dihydro derivative in 66% and 56% yield, respectively (99JCS(P1)3569). 

Chemical Name 3-(Diphenylmethoxy)-8-methyl-8-azabicyclo[3.2.1 ] octane methanesul-fonate... 

Chemical Name (6R-trans)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)thio] methyl)-8-oxo-7-([(1-H-tetrazol-1 -yl)acetyl] amino)-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid sodium salt... 

R,7R)-7-[2-[2-(2-Chioroacetamido)-4-thiazoiyl] -2-(methoxyimino)acetamidol 6-oxo-3-[ [(1,4,5,8-tetrahydro-4-methyi-5,8-dioxo-as-triazin-3-yi)thio] methyl] -5-thia-1 -azabicyclo [4.2.0] oct-2-ane-2-carboxylic acid... 

Chemical Nama 7-[(Aminophenylacetyl)amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ane-2-carboxylic acid... 

Benziloyloxy-1-azabicyclo[2.2.2] octane methobromide was prepared by adding 20 cc of a 30% solution of methyl bromide in ether to a solution of 2.5 g of 3-benziloyloxy-1-azabicyclo[2.2.2] octane in 20 cc of chloroform. After standing for 3 hours at room temperature and 15 hours at -i-5°C, a crystalline precipitate had formed. This was filtered off and recrystallized from a mixture of methanol, acetone, and ether prisms melting at 240° to 241°C. 

Chemical Name 6-[3-(2,6-dich orophenyl)-5-methyl-4-isoxazolecarboxamido] -S.G-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid sodium salt... 

Trimethyl-9-azabicyclo[3.3.1 ] nonan-30i-ol Methyl 0i,ai-di(2-thienyl)glycollate... 

A mixture of 1.0 g of 6,6,9-trimethyl-9-azabicyclo[3.3.1 ] nonan-3/3-ol, methyl 0i,0i-di-(2-thienyD-glycollate and 30 mg of metallic sodium is heated at 80°C to 90°C for about 2 hours under reduced pressure. After cooling, ether is added to the reaction mixture. The mixture is extracted with 10% hydrochloric acid. The aqueous layer is alkalified with sodium carbonate and reextracted with ethyl acetate. The extract is washed with water, dried and concentrated to dryness. The residue thus obtained is treated with hydrogen chloride by conventional manner. 2.0 g of the 0i,0i-di-(2-thienyl)glycollate of 6,6,9-trimethyl-9-azabicyclo-(3.3.1 ] nonan-3/3-ol hydrochloride are obtained. Yield 83%. 

Chemical Name 10-(1 -Azabicyclo[2.2.2] oct-3-yl-methyl )-1 OH-phenothiazine Common Name —... 

Azabicyclo[4.1.0]hept-3-enes, e. g. 13, are available from 1,4-dihydrobenzenes 12 by the route indicated, and are useful precursors for the synthesis of specifically substituted 1//-azepines free from isomeric contamination.61 For example, low temperature addition of bromine to bicycle 13 yields the dibromo derivative 14 which, with powdered sodium methoxide in tet-rahydrofuran, undergoes a double dehydrobromination followed by electrocyclic ring opening of the resulting 7-azabicyclo[4.1.0]hepta-2,4-diene 15 to give methyl l//-azepine-l-carboxylate (16). 

To a solution of methyl 3,4-dibromo-7-azabicyclo[4.1.0]heptane-7-carboxylate(l4 3 g, 9.6 mmol) in anhyd THF (100 mL) was added powdered NaOMe (1.04 g, 19.2 mmol) and the mixture was heated under reflux for 2 h. The solvent was removed under reduced pressure and the residue exlracted wilh F.l20 (300 ml,). The Et20 extract was washed with H20, dried (MgS04) and the solvent removed to give 16 as an orange oil yield 0.97 g (67%) bp 59-613C / 0.2 Torr. 

Curiously, 6-(chloromethyl)-4-methyl-2-methylene-3-phenyl-3-azabicyclo[4.1.0]hept-4-ene-l,5-dicarbonitrile (31), obtained from 4,4-bis(chloromethyl)-2,6-dimethyl-l-phenyl-1,4-dihydro-pyridine-3,5-dicarbonitrile, rearranges via 4-(chloromethyl)-7-methyl-2-methylene-l-phenyl-2, 5-dihydro-l//-azepine-3,6-dicarbonitrile (32) to yield the 4-(chloromethylene)-4,5-dihydro-1//-azepine 33 as the final product.127... 

A novel example of a 3,5-disubstituted 1//-azepine is methyl 12-azabicyclo[8.3.2]penta-deca-l0,l3,14-triene- 2-carboxylate (6) obtained, albeit in low yield, by the action of basegenerated (methoxycarbonyl)nitrene on [8]paracyclophane (5).147... 

A similar reaction occurs with methyl 3,5-bis(trimethylsilyl)-l//-azepine-l-carboxylate.146 Dimethyl 8,8-diacetyl-l,3,6-trimethyl-2-azabicyclo[3.2.1]oct-3-ene-4,7-dicarboxylatc (13) is produced in high yield by the action of the sodium salt of penta-2,4-dione on dimethyl 2,4,7-trimethyl-4//-azepine-3,6-dicarboxylate (12).132... 

Attempts to methylate the carbanion derived from ethyl 2-(diethylamino)-5-phenyl-3//-azepine-3-carboxylate (14) with iodomethane leads to the formation of the 3-azabicyclo[4.1.0]cyclo-hepta-2.4-diene 15.225... 

The tricarbonylchromium complex 6 of methyl 1/f-azepine-l-carboxylate undergoes photoin-duced [6 + 4] 7t-cycloadditions with dienes, e.g. 7, to give, after decomplexation with oxygen, azabicyclo[4.4.1]undecanes, e.g. 8, in high yields.276... 

Benzoyl-l-methyl-3,4-benzo-2-azabicyclo[3.2.0]hepta-3.6-diene (3) at 250"C yields exclusively l-benzoyl-2-mcthyl-l//-l-benzazepine (4).23 In contrast, silvcr(I) ion catalyzed ring expansion of 3 yields a mixture of the rearranged bicycle 5 (43 %), starting material (43 %), and the isomeric 1 H-l-benzazepines 4 (8%) and 6 (4%).23... 

The isomeric chloro-l-methylbenzo-2-azabicyclo[3.2.0]heptadienes 10a and 10b on heating under reflux in toluene rearrange in almost quantitative yields (90-95 %) to 9-chloro-l -methyl-1 H-benzazepine (11a) and its 6-chloro isomer lib, respectively.37... 

Methyl 3-Oxo-8-azabicyclo 3.2.11octane-8-carboxylate (7) Single Procedure170 ... 

Although useful, this synthesis of reduced quinoxalines has not been fully developed yet. 7-Azabicyclo[4.1.0]heptane (423, R = H) and glycine (424, Q = H) in refluxing aqueous ammonium chloride for 90 min gave octahydro-2(l//)-quinoxalinone (425, Q = R = H) in 40% yield." Similar treatment of 7-methyl-7-azabicyclo[4.1.0]heptane (423, R = Me) gave l-methyloctahydro-2(l//)-quinox-alinone (425, Q = H, R = Me) in 62% yield and 7-methyl-7-azabicyclo[4.1.0] heptane (423, R = Me) with L-alanine (424, R = Me) in refluxing aqueous ammonium chloride for 16 h gave two separable diastereoisomers of 1,3-dimethylocta-hydro-2(l//)-quinoxalinone (425, Q = R = Me), isolated as hydrochlorides in 26%... 

CN [2S-(2a,5a,6P)]-iV-methyl-D-asparaginyl-A-(2-carboxy-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]hept-6-yl)-D-2-(4-hydroxyphenyl)glycinamide... 

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